[unreadable] The immune response to a kidney transplant is triggered by specific recognition of graft antigens by T cells from the recipient. In association with this adaptive immune response, a key role has been suggested for non-specific inflammation in the pathogenesis of acute and chronic rejection. The aim of our program is to identify critical inflammatory mechanisms in transplant rejection that impact physiological functions of the allograft. As most current approaches to therapy exclusively target the alloantigen-dependent T cell response, we are investigating other components of the rejection response that could be modified to enhance graft function. Accordingly, we propose to study three discrete molecular pathways that shape the intensity and character of the inflammatory response in rejection. In Project 1 (PI: Coffman), signaling pathways used by G protein-coupled receptors (GPCRs) to promote rejection and graft injury will be dissected and characterized. Building on work accomplished during the last grant period, Project 1 will focus on 2 pathways for GPCR signaling: Gq proteins and small GTPase proteins of the Rho family. By contrast, Project 2 investigators (PI: Ting) will investigate a novel gene (Monarch-1) that has potent actions to block pro-inflammatory signals linked to the innate immune response. Activity of Monarch-1 attenuates transcription of cytokine genes such as IL-1 and blocks activation of NFkB, a key transcription factor in immune activation. Project 3 (PI: Koller) also examines molecular pathways constraining the intensity of inflammation, focusing on GPCR-dependent pathways that attenuate graft injury. Continuing an ongoing theme in the program, these studies will define the mechanisms and capacity of the prostanoid lipid mediator PGE2 to inhibit alloimmunity and graft rejection. By unraveling the molecular mechanisms underlying allograft injury, our goal is to develop translational paradigms for new diagnostic and therapeutic approaches to clinical problems in transplantation [unreadable] [unreadable]